Studies will define the physiological and biochemical regulation of deiodination of thyroid hormones within rat tissues. Because these processes contribute to the regulation of intracellular triiodothyronine (T3) concentrations, they represent one step in the expression of thyroid hormone action. Inasmuch as the regulation of deiodination within target tissues differs from organ to organ, it is hypothesized that the deiodination reactions permit tissues to meet their particular requirements for thyroid hormone under abnormal physiological conditions. One example is the potential for the brain to defend its intracellular T3 concentrations in hypothyroidism. Also, the studies will shed light on the mechanisms of thyroid hormone action in the brain because certain of the deiodinating enzyme activities depend on thyroid status, and can be used as quantitative indices of thyroid hormone effect. Radiometric assays will be employed to measure thyroxine (T4) 5'-deiodination, and 5-deiodination, 3,3',5'-(reverse)T3 5'-deiodination via two kinetically distinct pathways, and T3 5-deiodination. Specific protocols will examine the effects of glucocorticoids on the maturational patterns of these enzyme activities in pituitary and brain, the effects of congenital hypothyroidism on the high Km rT3 deiodinating pathway in brain and T3 5-deiodination in pituitary, the ontogenesis of enzyme activities in the lung, eye, brown fat and thyroid gland, and the effects of transient perinatal hyper- and hypothyroidism on pituitary T4 5'-deiodination in adulthood, when lifelong abnormalities of TSH regulation are known to occur. The physiological role of brain 5-deiodination will be tested using a selective inhibitor of the reaction as a probe. A functional association of the deiodinating reactions with specific neuronal systems will be sought, using selective chemical lesioning with 6-hydroxydopamine and 5,7-dihydroxytryptamine. Mechanisms of modulation of the brain 5'-deiodinating pathways by ATP and other nucleotides will be studied in vitro as will substrate and inhibitor specificity of the brain 5'-deiodinating pathways. Efforts will be made to characterize the physical properties of the brain 5-deiodinase. The mechanism by which thyrotropin increases 5'-deiodination in the thyroid gland will be studied.